A5008085384- Cardiomyopathy and Myosin Studies
- Cardiovascular Effects of Exercise
- RNA Research and Splicing
- Muscle Physiology and Disorders
- Cardiovascular Function and Risk Factors
- Cellular Mechanics and Interactions
- Congenital heart defects research
- Force Microscopy Techniques and Applications
- RNA and protein synthesis mechanisms
- Phosphodiesterase function and regulation
- Heart Failure Treatment and Management
- Cardiac Fibrosis and Remodeling
- Cardiac Structural Anomalies and Repair
- RNA modifications and cancer
- Genetic Neurodegenerative Diseases
- Viral Infections and Immunology Research
- Advanced Sensor and Energy Harvesting Materials
- Parathyroid Disorders and Treatments
- Bone health and treatments
- Cardiac electrophysiology and arrhythmias
- Bone Metabolism and Diseases
- Bone health and osteoporosis research
- Membrane-based Ion Separation Techniques
- Cardiovascular and exercise physiology
- Blood transfusion and management
University of Arizona
2016-2025
University of Missouri
2025
Johannes Gutenberg University Mainz
2019
University Medical Center of the Johannes Gutenberg University Mainz
2019
University Medical Center
2014
Amsterdam UMC Location Vrije Universiteit Amsterdam
2014
Janelia Research Campus
2013
Heidelberg University
2013
University Hospital Heidelberg
2013
Prapokklao Hospital
2012
Experimentally upregulating compliant titins has been suggested as a therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study. We investigate the effect of in novel mouse model with genetically altered splicing factor; integrative approaches were used from intact cardiomyocyte mechanics to pressure-volume analysis and Doppler echocardiography.Compliant upregulated through deletion RNA...
Background: Left ventricular (LV) stiffening contributes to heart failure with preserved ejection fraction (HFpEF), a syndrome no effective treatment options. Increasing the compliance of titin in has become possible recently through inhibition splicing factor RNA binding motif-20. Here, we investigated effects increasing mice diastolic dysfunction. Methods: Mice which recognition motif (RRM) one motif-20 alleles was floxed and that expressed MerCreMer transgene under control αMHC promoter...
The contractile machinery of heart and skeletal muscles has as an essential component the thick filament, comprised molecular motor myosin. filament is a precisely controlled length, defining thereby force level that generate how this varies with muscle length. It been speculated mechanism by which length involves giant protein titin, but no conclusive support for hypothesis exists. Here we show in mouse model deleted two titin's C-zone super-repeats, reduced cardiac muscles. In addition,...
Background— Diastolic dysfunction is a poorly understood but clinically pervasive syndrome that characterized by increased diastolic stiffness. Titin the main determinant of cellular passive However, physiological role tandem immunoglobulin (Ig) segment titin plays in stiffness generation and whether shortening this sufficient to cause need be established. Methods Results— We generated mouse model which 9 Ig-like domains (Ig3–Ig11) were deleted from proximal Ig spring region (IG KO). Exon...
Significance Mutations in titin are a major cause of heart failure, yet the functions large parts not understood. Here we studied titin’s I-band/A-band junction that has been proposed to be crucial for thick filament length control. We made mouse which IA was deleted. Super-resolution microscopy (structured illumination microscopy) revealed deleting increases strain on molecular spring elements without altering length. Single cell biomechanical measurements showed this passive stiffness...
A carbon fiber–based cell attachment and force measurement system was used to measure the diastolic stress–sarcomere length (SL) relation of mouse intact cardiomyocytes, before after addition actomyosin inhibitors (2,3-butanedione monoxime [BDM] or blebbistatin). Stress measured during interval twitching myocytes that were stretched at 100% base length/second. Diastolic stress increased close linear from 0 SL 1.85 µm 4.2 mN/mm2 2.1 µm. The BDM blebbistatin significantly lowered by ∼1.5 (at...
Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by but increased diastolic stiffness and abnormalities of filling. Although the prevalence HFpEF high continues to rise, no effective therapies exist; however, diabetic drug metformin has been associated improved function in patients. Here we determine therapeutic potential for improving mouse model HFpEF-like symptoms. We combine transverse aortic constriction (TAC) surgery deoxycorticosterone acetate...
Titin is a giant elastic protein that spans the half-sarcomere from Z-disk to M-band. It acts as molecular spring and mechanosensor has been linked striated muscle disease. The pathways govern titin-dependent cardiac growth contribute disease are diverse difficult dissect.To study titin deficiency versus dysfunction, authors generated compared specific knockouts (KOs) with progressive postnatal loss of complete by removing exon 2 (E2-KO) or an M-band truncation eliminates proper sarcomeric...
TTN (titin) is the third myofilament type of cardiac sarcomere and performs important functions that include generating passive tension. Changes in expression are associated with dysfunction, one main genes linked to dilated cardiomyopathy (DCM). DCM frequently changes N2BA (compliant isoform), 1 2 major isoforms found heart (the other isoform being N2B [stiff isoform]). Whether altered causes or a secondary change remains unclear. Here, we present mouse model, TtnΔ112-158 which specifically...
The incidence of HFpEF in women significantly increases following menopause. This trend cannot solely be attributed to chronological aging, as evidenced by the more gradual increase prevalence among men, suggesting that menopause is a provocative event for HFpEF. However, underlying mechanisms remain elusive and challenging investigate human subjects; moreover, an attempt create ovariectomized (OVX) mice was unsuccessful. In this study, we created animal model resembles undergoing natural...
Background: Low myocardial cGMP-PKG (cyclic guanosine monophosphate-protein kinase G) activity has been associated with increased cardiomyocyte diastolic stiffness in heart failure preserved ejection fraction. Cyclic monophosphate is mainly hydrolyzed by PDE (phosphodiesterases) 5a and 9a. Importantly, PDE9a expression reported to be upregulated human fraction myocardium chronic administration of a inhibitor reverses preestablished cardiac hypertrophy systolic dysfunction mice subjected...
Patients with heart failure preserved ejection fraction (HFpEF) experience elevated filling pressures and reduced ventricular compliance. The splicing factor RNA-binding motif 20 (RBM20) regulates the contour length of titin's spring region thereby determines passive stiffness cardiomyocytes. Inhibition RBM20 leads to super compliant titin isoforms (N2BAsc) that reduce stiffness.To determine therapeutic potential upregulating in an HFpEF-like state mouse.Constitutive inducible...
The heart has the ability to detect and respond changes in mechanical load through a process called mechanotransduction. In this study, we focused on investigating role of cardiac-specific N2B element within spring region titin, which been proposed function as mechanosensor. To assess its significance, conducted experiments using knockout (KO) mice wildtype (WT) mice, subjecting them three different conditions: 1) cardiac pressure overload induced by transverse aortic constriction (TAC), 2)...
Hyperprolactinemia caused by physiological or pathological conditions, such as those occurring during lactation and prolactinoma, respectively, results in progressive osteopenia. The underlying mechanisms, however, are controversial. Prolactin (PRL) may directly attenuate the functions of osteoblasts, since these bone cells express PRL receptors. present study therefore aimed to investigate effects on expression genes related osteoblast using quantitative real-time PCR technique. Herein, we...
Cardiac performance is tightly regulated at the cardiomyocyte level by sarcomere length, such that increases in length lead to sharply enhanced force generation same Ca2+ concentration. Length-dependent activation of myofilaments involves dynamic and complex interactions between a multitude thick- thin-filament components. Among these components, troponin, myosin, giant protein titin are likely be key players, but mechanism which proteins functionally linked has been elusive. Here, we...
Abstract Aims Heart failure with preserved ejection fraction (HFpEF) is associated reduced exercise capacity elicited by skeletal muscle (SM) alterations. Up to now, no clear medical treatment advice for HFpEF available. Identification of the ideal animal model mimicking human condition a critical step in developing and testing strategies. Several animals have been described, but most suitable terms comparability SM alterations patients unclear. The aim present study was investigate...
Titin is a giant protein spanning from the Z-disk to M-band of cardiac sarcomere. In I-band titin acts as molecular spring, contributing passive mechanical characteristics myocardium throughout heartbeat. RNA Binding Motif Protein 20 (RBM20) required for normal splicing, and its absence or altered function leads greater expression very large, more compliant N2BA isoform in Rbm20 homozygous mice (Rbm20ΔRRM) compared wild-type (WT) that almost exclusively express stiffer N2B isoform. Prior...
Titin's C-zone is an inextensible segment in titin, comprised of 11 super-repeats and located the cMyBP-C-containing region thick filament. Previously we showed that deletion titin's C1 C2 (TtnΔC1–2 model) results shorter filaments contractile dysfunction left ventricular (LV) chamber but unexpectedly LV diastolic stiffness normal. Here studied contraction-relaxation kinetics from time-varying elastance intact cardiomyocyte, cellular work loops cardiomyocytes, Ca2+ transients, cross-bridge...
KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C). Although is expressed in cardiac muscle, involvement unknown. Here, we constructed pedigrees three families with p.R408C variant. In 65 evaluated patients, 12% presented left ventricle dilatation, 29% ventricular ejection fraction< 50%, 8% atrial fibrillation, 9% tachycardia, and 20% repolarization abnormalities. Five received an...